The selective serotonin reuptake inhibitors and norepinephrine reuptake inhibitor class of antidepressants, which have the 3-aryloxy-3-arylpropylamine sub-structure, e.g. fluoxetine, tomoxetine, nisoxetine, norfluoxetine, and duloxetine, are among the most important pharmaceuticals for the treatment of psychiatric disorders such as anxiety and clinical depression (Drugs of the Future, 11, 134 (1986)). In addition, several members of this class have shown promise for the treatment of alcoholism, chronic pain and eating disorders such as obesity and bulimia (J. Med. Chem. 31, 1412 (1988)). Fluoxetine hydrochloride is marketed as its racemate (Prozac™, Eli Lilly Co.), but recently interest has been shown for marketing the more active (R)-enantiomer as an “Improved Chemical Entity” version of the drug. Tomoxetine was the first norepinephrine reuptake inhibiting antidepressant without strong affinity for α- or β-adrenergic receptor. The (R)-enantiomer, also called atomoxetine, is marketed as its hydrochloride salt under the name of Strattera™ and is purportedly ninefold more potent relative to the (S)-enantiomer.
There are several general synthetic methods reported in the prior art for the synthesis of 3-aryloxy-3-arylpropylamines 1 and their optically pure enantiomers. For example, U.S. Pat. No. 4,314,081 disclosed the racemic preparation of compounds of formula 1 via alkylation of substituted phenols with benzyl halide intermediates followed by further chemical elaboration. Tetrahedron Lett. 30, 5207-5210 (1989) disclosed the preparation of (R)-fluoxetine by the nucleophilic aromatic displacement reaction of (R)—N-methyl-3-hydroxy-3-phenylpropylamine with p-chlorobenzotrifluoride. A stereoselective route for the preparation of (S)-tomoxetine was disclosed in Tetrahedron, 53, 6739-6746 (1997), which utilized as a key step the coupling of lithiated o-cresol with a chiral iodoester to furnish an aryl ether intermediate. U.S. Pat. No. 5,068,432 disclosed the preparation of optically pure fluoxetine and tomoxetine using a Mitsunobu reaction for the coupling step.
More specifically, etherification by the nucleophilic aromatic displacement of 3-hydroxy-3-arylpropylamines 2 with aryl halides represents the most straightforward method of preparation.

For example, the reaction of N-methyl-3-hydroxy-3-phenylpropylamine with 4-trifluoromethyl-1-chlorobenzene in the presence of a strong base in dimethylsulfoxide (WO 94/00416), 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone (U.S. Pat. No. 5,847,214) have been reported to give N-methyl-(4-trifluoromethylphenoxy)-3-phenylpropylamine (fluoxetine). In addition, the reaction of an unactivated substrate, 2-fluorotoluene, with the alkoxide of (S)—N-methyl-3-phenyl-3-hydroxypropylamine in dimethylsulfoxide gave a modest yield and racemization (Tetrahedron Lett. 35, 1339-1342 (1994)). U.S. Pat. No. 6,541,668 disclosed that N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine) can be prepared by coupling 2-fluorotoluene with N-methyl-3-phenyl-3-hydroxypropylamine in 1,3-dimethyl-2-imidazolidinone in the presence of a strong base, such as potassium t-butoxide at about 110° C. These methods partially resolve some of the preparative problems associated with 3-aryloxy-3-arylpropylamines; however, these methods still suffer from various deficiencies including the use of expensive and undesired solvents, harsh reaction conditions (e.g., high temperature), the need for strong bases, and the loss of chirality when unactivated aryl halides and optically pure intermediates are used. Therefore, development of a process using a common solvent, less expensive reagents and mild reaction conditions is desired.
The stereospecific synthesis of 3-aryloxy-arylpropylamines is known in the art. In many of these methods, the asymmetry is introduced by utilizing enantiomers of 3-hydroxy-3-arylpropylamines, prepared by either stereospecific reduction of a ketone precursor or by resolution of the alcohol [J. Org. Chem. 53, 2916-2920 (1988); Tetrahedron Lett. 30, 5207-5210 (1989); U.S. Pat. No. 4,868,344; J. Org. Chem. 53, 4081-4084 (1988); and Tetrahedron Lett. 31, 7101 (1990)]. In general, when employing a specific enantiomer of the alcohol, the 3-aryloxy substituent is introduced by either the Mitsunobu reaction using a phenol or by nucleophilic aromatic displacement of the alkoxide on an aryl halide. However, due to the expense and difficulty of the Mitsunobu reaction at large scale, a commercial process that uses the nucleophilic aromatic displacement route is preferred.
Unfortunately, nucleophilic aromatic displacement reactions with 3-hydroxy-3-arylpropylamines normally require a strong base such as sodium hydride which may lead to racemization of the stereochemical center (J. Org. Chem. 53, 4081-4084 (1988); Tetrahedron Asymmetry, 3, 525-528 (1992); Tetrahedron Lett. 35, 1339-1342 (1994)). Also, low to modest yields are obtained when unactivated aryl halides are used. For example, the reaction of 2-fluorotoluene with the alkoxide of (S)—N-methyl-3-phenyl-3-hydroxypropylamine gives modest chemical yields of tomoxetine and epimerization of the chiral center was observed (Tetrahedron Lett. 35, 1339-1342 (1994)). For this reason, there are no stereospecific methods for the preparation of optically pure (R)—N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine (Atomoxetine) and its enantiomer, (S)—N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine by the direct aromatic displacement reaction of optically pure (R)- and (S)-3-hydroxy-3-phenylpropylamine with aryl halides. Therefore, a general method of producing optically active 3-aryloxy-3-arylpropylamines from optically active 3-hydroxy-3-arylpropylamines using a stereospecific aromatic displacement reaction, especially for the preparation of optically enriched (R)—N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine (Atomoxetine) and its enantiomer, (S)—N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine, is still attractive.
Methods of producing alkyl aryl ethers employing the traditional Williamson ether synthesis include direct nucleophilic substitution and the Cu(I)-catalyzed cross-coupling of alkoxides with aryl halides. However, these methods are limited in that they typically require activated aryl halides, large excesses of alkoxides, high reaction temperature and undesirable solvents. Recently, the palladium-catalyzed cross-coupling reaction of aryl halides with alcohols has been reported as an alternative method for the formation of the aryl-oxygen bond. Although this avoids many of the stated above limitations, the intermolecular reaction has been most successful using activated aryl halides.
A mild method for the etherification of aryl iodides and aliphatic alcohols that does not require the use of alkoxide bases was described in a recent article (Org. Lett. 4, 973-976 (2002)). The reaction was carried out in the presence of a catalytic amount of copper iodide and about 20 mole percent of the expensive (100-g=$309.50) and relatively toxic 1,10-phenanthroline catalyst. Also, a method of O-arylation of β-amino alcohols catalyzed by Cu(I) catalyst has also been reported (Org. Lett. 4, 3703-3706 (2002)), however all the examples in this article were for β-amino alcohol substrates and the authors report the complete lack of reactivity of simple alcohols under their conditions. From an industrial perspective, these copper-mediated reactions are attractive since copper reagents are relatively inexpensive and the reaction conditions are mild; however, the requirement of the toxic 1,10-phenanthroline as a catalyst is unfortunate from a pharmaceutical perspective.
With respect to the intermediates, preparations of 3-hydroxy-3-arylpropylamines and their optically pure enantiomers have been disclosed in the prior art. Among them, the most straightforward method is treatment of the hydroxy compound of formula 3 with the amine of formula 4 (Scheme 1), wherein LG is a leaving group.

However, although the conversion appears deceptively simple, it is well known that the synthetic value of this method is limited when one of R1 and R2 is hydrogen due to the concomitant over-alkylation, which results in mixtures of primary, secondary and tertiary amines, as well as quaternary ammonium salts (Tetrahedron, 57, 7785-7811 (2001)). This deficiency is compounded by the fact that compounds of formula 2 are difficult to purify since they are usually isolated as a viscous oil or low melting solid. Thus, in addition to the long-felt need for an efficient and cost-effective synthetic method for preparation of 3-aryloxy-3-propylamines, it is furthermore desirable to develop an efficient and cost-effective process to prepare compounds of formula 2 from compounds of formula 3 and isolate the compounds of formula 2 in pure form.